Reagents for the stereoselective generation of the chiral sidechain carbinol unit (C-15) in prostaglandin synthesis

ABSTRACT

A process for reducing trans-1-(2-carboxymethyl-3-hydroxy-5acyloxycyclopentyl)-1-octen-3-one- gamma -lactone to the corresponding 3-ol which makes use of trihydrocarbylborohydride reagents, some of which are new, e.g. lithium 2-thexyl-8-methyl2-borabicyclo(3,3,1)nonylhydride. A new process for producing this and other lithium thexyl-dihydrocarbylborohydrides which comprises contacting a thexyl-dihydrocarbylborane with an organolithium compound having a Beta -hydrogen atom.

United States Patent 1191 Corey Feb. 18, 1975 [76] Inventor: Elias J. Corey, Pfizer Inc., 235 E.

42nd St., Cambridge, Mass. 02134 22 Filed: Jan. 17, 1973 [21] Appl. No.: 324,511

Related US. Application Data [63] Continuation-in-part of Ser No. 117,748, Feb. 22,

1971, abandoned.

[52] US. Cl. 260/6065 B, 260/3433 [51] Int. Cl. C07f 5/02 [58] Field of Search 260/6065 B [56] References Cited UNITED STATES PATENTS 3,007,970 11/1961 Ashby 260/6065 B 3,055,943 9/1962 Honeycutt 260/6065 B 3,055,944 9/1962 Honeycutt 260/6065 B 3,055,945 9/1962 Honeycutt 1 260/6065 B 3,163,679 12/1964 Koster 260/6065 3,383,399 5/1968 Stafiej et a1. 260/6065 B OTHER PUBLICATIONS Zweifel et al., J.A.C.S., 86( 1964), p. 1076-1079. Brown et 211., J.A.C.S., 92(1970), p. 709-710.

Brown et 211., J.A.C.S., 86(1964), p. 1071-1075. Grundon et al., J. Chem. Soc. C., 1971, p. 2557-2559. Archer eta1., 1. Chem. Soc. C., 1971, p. 2560-2563.

Primary Examiner-Arthur P. Demers Attorney, Agent, or Firm-Connolly and Hutz [57] ABSTRACT A process for reducing trans-1-(2-carboxymethyl-3 hydroxy-5-acyloxycyc1opentyl)-1-octen-3-one-'ylactone to the corresponding 3-ol which makes use of trihydrocarbylborohydride reagents, some of which are new, e.g. lithium 2-thexy1-8-methy1-2- borabicyc10[3,3,1]nonylhydride, A new process for producing this and other lithium thexyl-dihydrocarbylborohydrides which comprises contacting a thexyl-dihydrocarbylborane with an organo-lithium compound having a B-hydrogen atom.

8 Claims, N0 Drawings REAGENTS FOR THE STEREOSELECTIVE GENERATION OF THE CHIRAL SIDECHAIN CARBINOL UNIT (C-15) IN PROSTAGLANDIN SYNTHESIS CROSS-REFERENCE TO RELATED APPLICATION 5 This application is a continuation-in-part of application, Ser. No. 117,748, filed Feb. 22, 1971 and now abandoned.

BACKGROUND OF THE INVENTION This invention relates to prostaglandin synthesis. The synthesis of prostaglandins E E F and P in optically active form constituted notable achievements (E. J. Corey, et al., J. Amer. Chem. Soc. 92:397, 1970; 42:2586, 1970; and earlier papers). These synthetic sequences are particularly characterized by mild and specific reaction conditions. Further progress in prostaglandin research was severely encumbered by the lack of a stereoselective means for the introduction of the chiral (asymmetric) carbon which bears the sidechain secondary alcohol function of the prostaglandins (C-I5). This chiral center is labelled in the formula below for prostaglandin E.

Ketone I Alcohol II Alcohol III 2 SUMMARY OF THE INVENTION The present invention comprises a process for the stereoselective reduction of the above key intermediate (Ketone I) in the synthesis of optically active prostaglandins; namely, it comprises the reduction of trans-]- (2-carboxymethyl-3-hydroxy-5-acyloxy-cyclopentyl)- l-octen-3-one y-lactone to the corresponding 3-01 by containing said 3-one in inert solvent and under inert atmosphere with at least equimolar proportions of a lithium trihydrocarbyl borohydride and a Lewis base at between about -50 and l50 C. until the reaction is substantially complete. A reaction temperature of be- 15 tween about 78 and 105 C. is especially preferred.

Stereoselectivity is enhanced at low temperatures. A ratio of as high as 4:1 of the desired S-configuration isomer to the R-configuration isomer is obtained by the process of this invention in contrast to a ratio of only 1:1 by prior art methods.

Preferred borohydrides for the new reduction reaction are: 1. lithium 2-thexyl-8-methyl-2- borobicyclo[3,3,l ]nonylhydride (Reagent IV) wherein R is alkyl having from one to six carbon atoms, cycloalkyl having from five to six carbon atoms, or phenyl;

wherein R is cycloalkyl having from five to six carbon atoms and R is alkyl having from one to six carbon atoms, cycloalkyl having from 5 to 6 carbon atoms, or phenyl;

50 4. lithium perhydro-9b-borophenalylhydride; and

wherein R is alkyl having from one to six carbon atoms, cycloalkyl having from five to six carbon atoms, or phenyl.

A wide variety of Lewis bases may be employed in the reaction, such as Lewis bases containing oxygen, nitrogen, sulfur or phosphorus, e.g., tertiary amines, or other proton acceptors. The choice of Lewis base is not critical, but hexamethyl phosphorus triamide is especially preferred. Any Lewis base which serves to suppress competing C=C reductions may be employed.

The acyloxy moiety may represent a wide variety of esters, with large ester groups such as pphenylhenzoate ester being especially preferred although acetate ester may heused. In fact, other types of protecting groups may be employed such as 2- tetrahydropyranyl or N,N-biphenylcarbamoyloxy. The protecting group employed is not a critical part of the invention.

The present invention further comprises, as new compositions of matter:

1. lithium 2-thexyl-8-methyl-2-borabicyclo[3,3,1] nonylhydride i CH /CH 9 CH3 CH3 Reagent IV 2. a borohydride of the formula:

wherein R is alkyl having from one to six carbon atoms, cycloalkyl having from five to six carbon atoms, or phenyl.

An especially preferred compound of this type is lithium 9-thexyl-9-borabicyclo[3,3,l]nonylhydride (Reagent V).

3. a borohydride of the formula:

R1 s L1 R -B-H wherein R is cycloalkyl having from five to six carbon atoms and R is alkyl having from one to six carbon atoms, cycloalkyl having from five to six carbon atoms, or phenyl.

The present invention further comprises the process for preparing those of the above mentioned new borohydrides wherein R is thexyl, by contacting a thexyl-dihydrocarbylborane in inert solvent with at least an equimolar proportion of an organo-lithium compound capable of donating a B hydrogen atom at a temperature of from about '20 to C. until the reaction is substantially complete. t-Alkyl lithium compounds having four to eight carbon atoms are preferred Li R B H I H CH CH wherein R is cycloalkyl having from five to six carbon atoms or phenyl; are especially preferred.

CH C CH3 CH Reagent VI C 2 \CH3 3 Reagent VII DETAILED DESCRIPTION OF THE INVENTION Preparation of trihydrocarbylboranes used in pro ducing trihydrocarbylborohydrides is performed by the general methods of Zweifel and Brown (J. Amer. Chem. Soc, :2066, 1963) and Brown and Pfaffenberger (J. Amer. Chem. 800., 89:5475. 1967). However, in the ease of Reagent VI these workers used d-limonene in the reaction. lt hasbeen found that d, l-limonene works equally well, and because of greater ease in obtaining the racemic compound, its use is preferred.

Those trihydrocarbylboranes having a thexyl group are converted to the corresponding borohydrides by the following new-procedurez Thexyl dihydrocarbylborane in reaction-inert solvent is cooled and stirred in an ice-bath over an atmosphere of dry nitrogen. Then a solution of t-butyllithium, or other organo-lithium compound having a B hydrogen atom, is added dropwise. The solution is stirred, at about 0 C. for 1 hour, to obtain the thexyl dihydrocarbylborohydride.

The preparation of the thexyl dihydrocarbylborohydride can be carried out in any of a variety of reactioninert solvents, but tetrahydrofuranpentane is particularly preferred.

The reduction of Ketone 1 (above) to Alcohols l1 and 111 is best carried out in an inert solvent such tetrahydrofuran-pentane; ether; 1,2-dimethoxyethane; or various combinations of these solvents, and in an inert atmosphere such as dry nitrogen or argon. The solvent should be one that remains fluid at the reaction temperature selected.

The Ketone l in tetrahydroguran/pentane solution, for example, is added to the reaction vessel. A Lewis base, such as hexamethylphosphorus amide, is then added to the solution. The amount used should be in at least a 1:1 molar ratio with Ketone l, but large excesses of up to fold are permissible. Other Lewis bases such as tertiary amines can also be effectively used in this reaction. Then the reducing agent, e.g., Reagent IV or V is added, also preferably in at least a 1:1 molar ratio with Ketone 1, and the reaction is allowed to proceed at about -100 to 105 C. A temperature as high as 78 C. will yield a useful proportion of the desired isomer. but reaction temperatures substantially higher than 78 C. cause the production ofa large amount of the unwanted R-configuration isomer (Alcohol 111). Temperatures as low as 150 C. can be tolerated. When the reaction is substantially complete, the reaction is quenched with acid, e.g. lN-aqueous HC] and the mixture is diluted with water and extracted with inert solvent, e.g. ether. Evaporation of solvent after drying affords a 90% yield of a mixture of Alcohols 11 and 111 in a ratio of as high as 4:1 depending upon the reducing agent employed. The alcohols may be separated by conventional chromatography using silica gel.

A variety of lithium trihydrocarbylborohydrides may be used as reducing agents in the reduction of Ketone l to Alcohol 11 and 111, but those which have large hydrocarbyl moieties e.g., thexyl and limonyl attached to the boron, are especially, effective in producing the desired ratio of Alcohol 11 to Alcohol 111.

Other lithium trihydrocarbylborohydride reducing agents which are useful in this respect, and which are new compounds of this invention, are those of the formula:

wherein R is alkyl (i.e., having from one to eight are preferably from one to six carbon atoms), cycloalkyl of five to six carbon atoms, or phenyl. Such compounds are prepared by the direct reaction of RLi to the corresponding borane (see Knights and Brown, J. Amer. Chem. Soc. 90:5280, 1968 for borane preparation). In the case where R thexyl, the reaction involving the ,8 hydrogen atom of an organo-lithium compound should be employed, as previously described.

Other lithium trihydrocarbylborohydride reducing agents. also new compounds of this invention, are of the formula:

wherein R is cycloalkyl of five to six carbon atoms and R is alkyl having from one to six carbon atoms, cycloal kyl of five to six carbon atoms or phenyl. These reagents are prepared by the direct reaction of RLi with appropriate boranes such as are described by Brown in Hydroboration, W. A. Benjamin, 1nc., New York (1962).

Still another example of a lithium trihyd rocarbylborohydride reducing agent useful in the new process of this invention is lithium perhydro-9bborophenalylhydride. The preparation of this borohydride is given by Brown and Dickason, J. Amer. Chem. Soc. 92:709 (1970).

Other reagents which have been used to reduce Ketone 1 to Alcohols II and 111 are of the formula:

wherein R is alkyl having from one to six carbon atoms, cycloalkyl having from five to six carbon atoms, or phenyl. These compounds are made from the reaction of RLi and boranes as prepared by Brown, et al. J. Amer. Chem. Soc. 86:1071 (1964).

The following examples are given by way of illustration and are not intended to depart from the spirit and scope of the appended claims.

EXAMPLE 1 A 50-ml. round-bottomed flask equipped with a magnetic stirring bar was closed with a rubber septum and flamed in a stream of dry nitrogen. It was subsequently cooled in a bath at -10 and was thereafter maintained over an atmosphere of nitrogen by the balloon technique. In the flask was placed a solution of diborane in tetrahydrofuran (25.0 ml., 26.25 mmolo), and 2,3- dimethyl-Z-butene (26.25 mmol, 2,20 g., 3.1 ml.) was added drop by drop from a hypodermic syringe in the course of 15.0 min. The resulting homogeneous solution was stirred for a few minutes and was then ready to use. The molarity estimated by the measurement of the gas evolved on decomposition of aliquots with tetrahydrofuran-water-ethylene glycol (121:1) was 0.931.

In a l00-ml. round-bottomed flask equipped with a magnetic stirring bar and flushed with dry nitrogen was placed dry tetrahydrofuran. The flask was then cooled and was efficiently stirred in an ice bath. Then 10.0 ml. each of 0.931 M solutions of thexylborane and (I) or d-limonene in tetrahydrofuran were added simultaneously and at the same rate from identical 10.0 ml. sy-

ringes in the course of 50 min. with the aid of a double syringe pump. After stirring for 1.0 hr. at 0, the solution was ready for use in the next step of the reaction.

The solution of the borane Vl (9.31 mmol) was stirred in an ice-bath over an atmosphere of dry nitrogen. Then a solution of t-butyllithium (9.3 mmol, 4.27 ml.) in pentane was added drop by drop in the course of 5.0 min. A transient canary yellow color was produced and disappeared as each drop fell into the reaction vessel. The resulting colorless, homogeneous solution was then stirred for 1.0 hr. at 0 prior to use. The

product obtained was borohydride IV, lithium 2-thexyl- 8-methyl-2-borabicyclo[3,3,1]nonylhydride.

The infrared absorption spectrum of this solution showed a broad, medium intensity absorption at 4.90 [1.(2041 cm) due to -Bl-1. Such an absorption is exhibited by trialkylborohydrides (see H. C. Brown and W. C. Dickason, J. Amer. Chem. Soc., 92,709, 1970, and P. Binger, G. Benedikt, G. W. Rotermund, and R. Koster, Ann., 717,21, 1968).

The above procedure was repeated substituting 9- thexyl-9-borabicyclo-[3,3,1]nonane (prepared by the method of Knights and Brown, J. Amer. Chem. Soc. 90:5280, 1968), for the above mentioned borane, to produce 9-thexyl-9-borabicyclo[3,3,1]nonylhydride.

EXAMPLE II In a 25-ml. round-bottomed flask equipped with a magnetic stirring bar wasa placed Ketone I (111.2 mg, 0.25 mmol). The flask was then closed with a rubber septum, flushed with dry nitrogen, and subsequently maintained under an atmosphere of nitrogen. Then dry tetrahydrofuran (2.5 ml.) was added; the solution was cooled and stirred in a bath at -lO to 105, and hexamethyl-phosphorus amide (5.0 mmol, 809 mg, 0.91 ml.) was introduced from a hypodermic syringe. Finally, the solution of borohydride IV described in the previous example (7.5 ml., 1.31 mmol) was added drop by drop in the course of 15 minutes. The reaction was allowed to proceed for 3.0 hr, at 100 to -105 and was then quenched by the addition of 7 ml. of 1N- hydrochloric acid and warmed to C. It was then diluted with ice water (30 ml.) and extracted with ether (4 X 30 ml.). The extracts were then combined, washed successively with water (3 X ml.) and a saturated sodium chloride solution (2 X 10 ml.), dried (anhydrous MgSO filtered, and evaporated at room temperature in vacuo. The residual oil was spotted on two tlc plates (2 X 200 X 200 mm), and the plates were developed two or three times with ethyl acetate benzene (1:3). The bands corresponding to the alcohols 2 and 3 were separately extracted with ethyl acetate-methanol (95:5), and the extracts were evaporated at room temperature in vacuo. They were redissolved in small amounts of ethyl acetate and washed with distilled .water to remove the small amounts of entrained silica.

These solutions were then dried (anhydrous MgSO and evaporated affording Alcohol 11 (82.61 mg) and Alcohol 111 (20.31 mg.). The total yield of" and III was 92.37%. The nuclear magnetic resonance and infrared spectra of II and 111 thus prepared were identical with those of authentic samples.

EXAMPLE III Following the procedures of Example 11 the reducing agents given below were used to reduce Ketone 1 to Alcohol 1i and Alcohol 111. The ratio of Alcohol II to Alcohol III obtained in the reductions was from 2.8 to 3.0.

REDUCING AGENT wherein R is methyl, t-butyl, thexyl and phenyl.

These reducing agents were prepared by the methods of Knights and Brown, J. Amer. Chem. Soc. :5280 (1968) followed by conventional RLi addition, except for the case of R thexyl which was prepared in Example I.

EXAMPLE IV Following the procedures of Example II the reducing agents given below were used to reduce Ketonel to Alcohol II and Alcohol III. The ratio of Alcohol Ii to Alcohol III obtained in the reductions was from 1.8 to 2.2.

wherein R is methyl, isopropyl, t-butyl and cyclohexyl. For preparation of the borohydrides see Brown, et al., J. Amer. Chem. Soc. 86:1071 (1964), followed by conventional RLi addition.

EXAMPLE V Following the procedures of Example 11 the reducing agents given below were used to reduce Ketone I to Alcohol II and Alcohol III. The ratio of Alcohol 11 to Alcohol III obtained in the reductions was from 1.8 to 2.8.

' Ci Lie n -s-u wherein R is cyclohexyl and R is methyl, t-butyl and phenyl. These reducing agents are prepared by the gen- I eral methods of Brown in Hydroboratio'n,

published by W. A. Benjamin, Inc., New York, 1962, followed by conventional RLi addition.

EXAMPLE V1 mole (10 mls of a 1 molar solution in tetrahydrofuran) or borane to which 0.03 mole cyclopentene (2.04 g) was added dropwise at 20 C. under a nitrogen atmosphere. After stirring for 1 hour at 0, 0.01 mole of tbutyllithium (7.14 ml of 1.4 molar solution in pentane) was added dropwise over 10 minutes and the solution stirred for an additional 1 hour at 0 to give the tricyclope'ntyl lithium borohydride (0.5 molar solution).

EXAMPLE VIII To a cooled solution of 0.14 g ketone (I) in 5 ml tet- 9 rahydrofuran at 75 was added 0.5 ml of tricyclopentyl borohydride (1.23 molar solution) of Example VII over a period of 15 minutes. The reaction was stirred l 4. The process for preparing a lithium thexyl dihydrocarbyl borohydride selected from the group consisting of those of the formulae:

an additional minutes and quenched by adding 3 ml of 40% acetic acid. The reaction was allowed to come to room temperature and extracted with CH Cl The organic layer was washed with brine, dried (Na So and concentrated. The residue chromatographed on silica gel afforded 80 mg alcohol II, 39 mg alcohol Ill and 6 mg mixed fraction of alcohols 11 and Ill.

What is claimed is:

1. Lithium 2-thexyl-8methyl-Z-borabicyclo [3,3,1]- nonylhydride.

2. A borohydride of the formula wherein R is alkyl having from one to six carbon atoms, cycloalkyl having from five to six carbon atoms or phenyl.

3. The borohydride of claim 2 wherein R is thexyl.

wherein R is cycloalkyl having from five to six carbon atoms or phenyl; which process comprises contacting the corresponding borane in inert solvent with at least an equimolar proportion of a t-alkyl lithium compound having from four to eight carbon atoms and having a 6 hydrogen atom, at a temperature of from about 20 to +20C. until the reaction is substantially complete.

5. The process of claim 4 wherein said contacting is conducted at about 0 C.

6. The process of claim 4 wherein said t-alkyl-lithium compound is t-butyllithium.

7. The process of claim 4 wherein said borane is 2- thexyl-8-methyl-2-borabicyclo[3,3,l ]nonane.

8. The process of claim 4 wherein said borane is 9- UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3, 867,460

DATED February 18, 1975 INVENTOR(S) Elias Corey It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown betow:

Title page, first column, opposite [76] should read Inventor: Elias J. Corey, 20 Avon Hill Cambridge, Mass. 02134 Signed and Scaled this twenty-first Day of October 1975 [SEAL] Attest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner oj'Patents and Trademarks Notice of Adverse Decision in Interference In Interference No. 99,382, involving Patent No. 3,867 ,460, E. J. Corey, REAGENTS FOR THE STEREOSELECTIVE GENERATION OF THE CHIRAL SIDEOHAIN CARBINOL UNIT (0-15) IN PROSTAGLAND-IN SYNTHESIS, final judgment adverse to the patentee Was rendered Feb. 17, 1977, as to claims 1-3.

[Ofiicz'wl Gazette July 5, 1.977.] 

1. LITHIUM 2-THEXYL-8-METHYL-2-BORABICYCLO (3,3,1)NONYLHYDRIDE.
 2. A borohydride of the formula
 3. The borohydride of claim 2 wherein R is thexyl.
 4. The process for preparing a lithium thexyl dihydrocarbyl borohydride selected from the group consisting of those of the formulae:
 5. The process of claim 4 wherein said contacting is conducted at about 0* C.
 6. The process of claim 4 wherein said t-alkyl-lithium compound is t-butyllithium.
 7. The process of claim 4 wherein said borane is 2-thexyl-8-methyl-2-borabicyclo(3,3,1)nonane.
 8. The process of claim 4 wherein said borane is 9-thexyl-9-borabicyclo(3,3,1)nonane. 